Can a Single Measurement of Apixaban Levels Identify Patients at Risk of Overexposure? A Prospective Cohort Study

Abstract

Background Patients with atrial fibrillation (AF) are frequently treated with apixaban 2.5-mg twice daily (BID) off-label, presumably to reduce the bleeding risk. However, this approach has the potential to increase the risk of ischemic stroke. If a single measurement could reliably identify patients with high drug levels, the increased stroke risk may be mitigated by confining off-label dose reduction to such patients. Objectives This study aimed to determine whether a single high apixaban level is predictive of a similarly high level when the test is repeated in 2 months. Methods In this prospective cohort study of clinic patients receiving apixaban 5-mg BID for AF or venous thromboembolism, peak and trough apixaban levels were measured using the STA-Liquid anti-Xa assay at baseline and 2 months. We calculated the proportions of patients with levels that remained in the upper quintile. Results Of 100 enrolled patients, 82 came for a second visit, 55 of whom were treated with apixaban 5-mg BID. Seven (63.6%, 95% confidence interval [CI]: 35.4–84.8%) and nine (81.8%, 95% CI: 52.3–94.9%) of 11 patients with a baseline trough and peak level in the upper quintile, respectively, had a subsequent level that remained within this range. Only one (9.1%, 95% CI: 1.6–37.7%) patient had a subsequent level that fell just lower than the median. Conclusion The trough and peak levels of apixaban in patients who have a high level on a single occasion, usually remain high when the assay is repeated in 2 months. Accordingly, the finding of a high apixaban level in patients deemed to be at high risk of bleeding, allows physicians contemplating off-label use of the 2.5-mg BID dose to limit its use to selected patients who are less likely to be exposed to an increased risk of thrombosis.

Clinical Studies with Anticoagulants that Have Changed Clinical Practice

“…On the other hand, if the levels fall outside the usual on-therapy range, we consider an appropriate dose adjustment if the DOAC remains the most appropriate anticoagulant option. 78…”

“…On the other hand, if the levels fall outside the usual on-therapy range, we consider an appropriate dose adjustment if the DOAC remains the most appropriate anticoagulant option. 78 Indications for which Direct Oral Anticoagulants Are Less Effective than Older Anticoagulants There are at least three clinical indications for which DOACs seem to be less effective than VKAs. The first is the prevention of thrombosis on artificial surfaces (e.g., in patients with a mechanical heart valve or left ventricular assist device), 79,80 the second is the treatment of antiphospholipid syndrome, [81][82][83][84] and the third is the prevention of stroke in patients with rheumatic atrial fibrillation (►Table 4).…”

Letter by de Vries et al Regarding Article “Off-Label Under- and Overdosing of Direct Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis”

“…However, it might be appropriate to consider off-label dose reducing in high-risk patients if they were underrepresented in studies that established and validated the dosing recommendations. 2–4 Examples of such higher-risk patients include those with prior or recurrent major bleeding, those with extreme clinical characteristics (the very elderly or frail, the unusually underweight, those with severe chronic kidney disease), and those treated with drugs that result in very high direct oral anticoagulant exposure. 2–4…”

“…Dose-ranging trials of all 4 direct oral anticoagulants have shown a relationship between dose and outcome, 2 so patients given a lower dose off-label in error are exposed to an unnecessary high thromboembolic risk. However, it might be appropriate to consider off-label dose reducing in high-risk patients if they were underrepresented in studies that established and validated the dosing recommendations.…”

“…2–4 Examples of such higher-risk patients include those with prior or recurrent major bleeding, those with extreme clinical characteristics (the very elderly or frail, the unusually underweight, those with severe chronic kidney disease), and those treated with drugs that result in very high direct oral anticoagulant exposure. 2–4…”